This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goals of this study are to: 1. Develop lentiviral vectors that contain RNAi sequences that target hyaluronan synthases and CD44 in reactive astrocytes in demyelinating lesions. Using primary cultures of mouse cortical astrocytes, we will test RNAi sequences for their ability to inhibit the expression of different hyaluronan (HA) synthases and CD44;clone optimal RNAi sequences into lentiviral vectors bearing the GFAP promoter;and test the efficacy of each lentiviral construct in co-cultures of astrocytes and OPCS;2. Test the ability of lentiviral constructs driving HA synthase and CD44 RNAi sequences to promote remyelination in vivo. Using the lentiviral constructs optimized in aim 1, we will test if constructs that inhibit the expression of HA synthases, CD44, or CD44 and HA synthases prevent HA accumulation and promote OPC maturation and remyelination in the white matter of a transgenic mouse in which HA accumulation is accompanied by CNS dysmyelination.